1. Field of the Invention
The present invention relates to methods of treating different types of cancer cells either in vitro or in vivo by treatment with a tripeptide in which the amino acid dichlorodiethylaminophenylalanine is bonded by peptide links to parafluorophenylalanine and methionine.
2. Prior Art
Chemotherapy has been and still is an object of intense research. Certain positive results have undoubtedly been achieved, especially by means of polychemotherapy realized byassociating different active substances according to carefully developed protocols. However, the ideal therapy has not been found. The need to find new active substances has been particularly emphasized. All the foregoing justifies continuous research directed toward preparing new chemotherapeutic compounds active against cancerous tumors. There are already known peptides having anti-tumor activity, consisting of both normal and antimetabolic amino acids, coupled by means of a peptide bond. Such peptides have for years been in therapeutic use with favorable results both in monochemotherapy and in polychemotherapy.
As disclosed in copending U.S. application Ser. No. 311,646, a new family of antitumor compounds is characterized in that each compound comprises the amino acids dichlorodiethylaminophenylalanine, parafluorophenylalanine and methionine bonded together by CO--NH peptide links formed by the respective amino and carboxyl groups of the said amino acids. All possible permutations of the three amino acids are set forth as follows:
1. pFPne. MPhe. Met PA0 2. pFPhe. Met. MPhe PA0 3. MPhe. pFPhe. Met PA0 4. MPhe. Met. p.FPhe PA0 5. Met. pFPhe. MPhe PA0 6. Met. MPhe. p.FPhe PA0 (a) 3-(p-fluorophenyl)-L-alanyl-3[m-bis(2-chloroethyl)-aminophenyl]-L-alanyl-L -methionine PA0 (b) 3-[m-bis(2-chloroethyl)aminophenyl]-L-alanyl-3-(p-fluorophenyl)-L-alanyl-L -methionine PA0 (c) 3-(p-fluorophenyl)-L-alanyl-L-methionyl-3-[m-bis(2-chloroethyl)aminophenyl ]-L-alanine PA0 (d) 3-[m-bis(2-chloroethyl)aminophenyl]-L-alanyl-L-methionyl-3-(p-fluorophenyl )-L-alanine PA0 (e) L-methionyl-3-(p-fluorophenyl)-L-alanyl-3-[m-bis(2-chloroethyl)aminophenyl ]-L-alanine PA0 (f) L-methionyl-3-[m-bis(2-chloroethyl)aminophenyl]-L-alanyl-3-(p-fluorophenyl )-L-alanine.
wherein "MPhe" indicates the amino acid dichlorodiethylaminophenylalanine having the structural formula: ##STR1## and wherein "pFPhe" indicates the amino acid parafluorophenylalanine having the structural formula: ##STR2## and wherein "Met" indicates the amino acid methionine having the structural formula: ##STR3## The above-identified tripeptides are useful in the treatment of malignant tumors. The above noted tripeptides are prepared by condensing one of the amino acids having a blocked amine group with another of said amino acids having a blocked carboxyl group with the aid of dicyclohexylcarbodiimide; removing one of the blocking groups to form a dipeptide having a blocked amine or carboxyl group; and condensing the dipeptide with the third amino acid to form the tripeptide with the aid of dicyclohexylcarbodiimide. Compounds of the tripeptide can also be formed, such as compound, by esterifying the tripeptide; and introducing hydrogenchloride.
To further illustrate the synthesis of a tripeptide compound, the following specific process is set forth.